Cardiovascular magnetic resonance (CMR) is currently a gold standard imaging test for various cardiovascular pathologies. This is due to ongoing technological advances that have shortened acquisition times with improved image quality and the convincing results from larger clinical trials. Rather than a single technique, CMR consists of several techniques that can be performed separately or in various combinations during a patient examination.

Use of contrast enhanced imaging techniques makes it a unique modality allowing:

Perfusion assessment,

Superior non-invasive tissue characterisation and

Angiographic studies.

Contrast agents in CMR

All the contrast agents used for CMR essentially contain Gadolinium (a lanthanide group element) as a paramagnetic Gd3+ ion, which has seven unpaired electrons in its half-filled 4 f outer shell. Gd3+ has a long electronic relaxation time based on its totally symmetric S state making it well suited for use as an MR contrast agent. It accelerates the relaxation of the water molecules present in the tissue, giving rise to an enhanced signal on T1-weighted images and, together with appropriate sequence parameters, an improved image contrast. (1)

Mechanism of hyperenhancement

The superior tissue characterisation is possible due to the varied hyperenhancement patterns seen in different cardiovascular conditions. The mechanism of hyperenhanement is based on two principles. Firstly, gadolinium chelates are inert extra cellular contrast agents which cannot cross the intact/normal myocyte cell membranes.(2) Secondly, in normal myocardium, myocytes are densely packed and thus myocyte intracellular space forms the majority (85%) of the volume. (3) Hence, the volume of distribution of gadolinium in a hypothetical voxel of normal myocardium is small, and the overall number of gadolinium molecules is low. In the setting of acute pathology (like myocardial infarction), there is myocyte membrane rupture, which allows additional gadolinium to diffuse into what was previously intracellular space. This in turn results in increased gadolinium concentration and therefore hyperenhancement. In the setting of chronic pathologies (like chronic infarct or cardiomyopathies), myocytes are replaced with collagenous scar. As a result interstitial space is expanded which again leads to increased gadolinium concentration and therefore hyperenhancement. (4)
The mechanism of myocardial hyperenhancement is demonstrated in Figure 1.

Fig 1: Diagram showing the mechanism of gadolinium enhancement (5)

Types of gadolinium based contrast agents (GBCAs)
The harmful effects of Gd3+ are suppressed by encasing it in an organic chelator. A variety of such chelators have been approved for use. The contrast agents in clinical use are classified into the linear chelator group or macrocyclic chelator group.
Linear:

Omniscan (Non-ionic) – Gadodiamide

Optimark (non-ionic) – Gadoversetamide

Magnevist (ionic) – Gadopentate

Multihance (ionic) – Gadobenate

Primovist (ionic) – Gadoxetate

Vasovist (ionic) – Gadofosvescet

Macrocyclic:

Gadovist (non-ionic) – Gadobutrol

Prohance (non-ionic) – Gadoteridol

Dotarem (ionic) - Gadoterate

Nephrogenic sytemic fibrosis

In the early days of contrast MRI, GBCAs were considered safe with only rare side effects like allergic reactions or local irritation from extravasations. However, a new disease called Nephrogenic Fibrosing Dermopathy emerged in 1997. Cowper in 2001 described the disease (6). Its association with GBCA exposure was strongly suspected since 2006 (7,8). Later this condition was renamed Nephrogenic Systemic Fibrosis (NSF) when involvement of internal organs was discovered. The NSF Registry, www.icnfdr.org so far identified over 380 cases, all occurring in patients on dialysis or with severe renal dysfunction (9). However since the connection between NSF and GBCAs has become known changes in MRI protocols with the focus on prevention has led to a decrease in NSF incidence. In spite of continued use of GBCA, virtually no new NSF cases since 2008 has been reported (both in patients with normal renal function and patients with renal impairment) (10,11).

Association of NSF with kidney impairment

GBCA are more-or-less entirely excreted via the kidneys. In patients with kidney disease, administered GBCA will require more time to exit the body. If there is no residual urine output, the only way such agents can exit the body is through diaysis procedures. In patients with normal kidney function, GBCA are considered safe because the bond between the toxic Gd atom and its ligand molecule is extremely strong and because the GBCA molecule is flushed from the body so rapidly. There is a small risk that Gd atoms could dissociate (unbind) from their carrier ligands, but if this occurred, Gd (which acts much like calcium atoms in the body) would likely bind to readily available phosphates and form insoluble molecules. In patients who receive large doses of GBCA and do not undergo rapid and effective dialysis, there is a risk that larger amounts of these gadolinium compounds could develop and remain in the body in a form that is not readily removable.

Incidence and Prevalence

The majority of NSF cases have been reported in patients undergoing GBCA enhanced imaging. Interestingly about 5% of NSF cases showed no traceable prior exposure to GBCAs (12). The GBCAs are a cofactor in developing NSF. The incidence depends on kidney impairment (especially if dialysis or kidney impaired patients develop sepsis or proinflammatory process) (13,14) and also on the type and dose of GBCA. Patients who receive a GBCA dose (e.g. 0.1mmol/kg) overall incidence is near zero, regardless of their renal function.
The majority of reported cases are associated with non-ionic linear contrast agents (Gadodiamide or Gadoversetamide). Another agent associated with NSF is Gadopentate dimeglumine, but there are markedly fewer cases with Gadopentate dimeglumine than with Gadodiamide. No case of NSF has been reported with the other GBCAs.
On the basis of current evidence, the GBCAs are classified as: (15)

In UK Gadovist and Dotarem are the most commonly used CMR contrast agent.

Brand name (generic name)

Chemical structure

Charge

Elimination pathway

Protein binding

Cases of NSF

Omniscan
(gadodiamide)

Linear

Non-ionic

Kidney

None

Yes

OptiMARK
(gadoversetamide)

Linear

Non-ionic

Kidney

None

Yes

Magnevist
(gadopentetate dimeglumine)

Linear

Ionic

Kidney

None

Yes

MultiHance
(gadobenate dimeglumine)

Linear

Ionic

97% Kidney
3% Bile

<5%

Yes

Primovist
(gadoxetic acid disodium salt)

Linear

Ionic

50% Kidney
50% Bile

<15%

No

Vasovist
(gadofosveset trisodium)

Linear

Ionic

91% Kidney
9% Bile

>85%

No

ProHance
(gadoteridol)

Cyclic

Non-ionic

Kidney

None

No

Gadovist
(gadobutrol)

Cyclic

Non-ionic

Kidney

None

No

Dotarem
(gadoterate meglumine)

Cyclic

Ionic

Kidney

None

No

Table 1: Properties of GBCAs and reported cases of NSF (16)

Clinical Features and Treatment of NSF

NSF usually present with indurated plaque like skin lesions, typically beginning on the distal extremities later on spreading to the upper extremities, trunk and eye. The plaques are symmetrical and are described as brawny, with hyperpigmented adjoining areas. Sharp pain as well as pruritus, causalgias and paresthesias in affected areas is a common symptom. Stiffness and joint contractures can lead to decreased mobility. In an estimated 5% of cases the progression is rapid leading to immobility and in a few instances death has been attributed to NSF. Other internal organs can be affected including lung, heart, liver, bones and kidneys. The diagnosis can be confirmed with a deep punch skin biopsy. (17)

There is no proven definitive therapy for the treatment of NSF and the treatment options are limited to symptomatic relief. However there are reports that NSF can be cured with restoration of normal kidney function by renal transplantation. Literature review suggests the role of other therapy options like extracorporal photopheresis, plasmapheris, UV-A1 Therapy, high dose intravenous Immunoglobulins, Imatinib Mesylate, Rabamycine and Pentoxifylline. Considering the small numbers of case reports and the fact that NSF can possibly be avoided by preventive measures, the focus should be primarily on prevention. (1)

Do not repeat administration of any GBCA during a single imaging session

MHRA UK (Jan 2010) Recommendations (16)

Advice for healthcare professionals:
The following risk-minimisation measures should be used for gadolinium containing contrast agents:

1. Renal-function monitoring
Renal function should be tested in all patients receiving high-risk agents, and is generally advisable for patients receiving medium-risk or low-risk agents. It is particularly important to screen patients aged 65 years or older

2. Renal impairment
For patients with severe renal impairment (glomerular filtration rate [GFR] <30 mL/min/1·73m2), use of a high-risk agent is contraindicated. If use of a medium-risk agent cannot be avoided or if it is necessary to use a low-risk agent, a single lowest dose possible can be used and should not be repeated for at least 7 days
For patients with moderate renal impairment (GFR 30–59 mL/min/1·73 m2), if it is necessary to use a high-risk agent a single lowest dose possible can be used and should not be repeated for at least 7 days

3. Perioperative liver-transplantation period
Use of a high-risk agent is contraindicated. If use of a medium-risk agent cannot be avoided or if it is necessary to use a low-risk agent, a single lowest dose possible can be used and should not be repeated for at least 7 days

4. Neonates
Use of a high-risk agent is contraindicated. For medium-risk or low-risk agents, use a single lowest possible dose and do not repeat for at least 7 days

5. Infants
Use a single lowest dose of agent possible and do not repeat for at least 7 days

6. Breastfeeding
Discontinue for at least 24 hours after use of a high-risk agent. The decision of whether to continue or suspend breastfeeding for 24 hours after use of a medium-risk or low-risk agent should be at your discretion in consultation with the mother

7. Pregnancy
Use of any gadolinium-containing contrast agent is not recommended unless absolutely necessary

8. Haemodialysis
There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis

9. Recording of the agent used
Peel-off tracking labels found on the vials, syringes, or bottles and stick onto the patient record to accurately record the name of the gadolinium contrast agent used. The dose used should also be recorded

Contrast enhanced CMR is a safe and effective imaging modality. Although the chance of developing NSF is rare the focus should be on prevention.
Points to remember:
a. GBCA is a risk factor for NSF
b. Use low-risk GBCAs if possible
c. Use minimum dose
d. Avoid in patients with impaired kidney function
e. In patients already on dialysis consider prompt dialysis